2, 3-acetonide derivatives of androstanes



United States Patent Ofiice 3,066,138 2,3-ACETONIDE DERIVATIVES F ANDROSTANES John Edwards, Mexico City, Mexico, assignor, by mesne assignments, to Syntex Corporation, a corporation of Panama 7 No Drawing. Filed Nov. 17, 1961, Ser. No. 153,242 22 Claims. (Cl. 260-23955) The present invention relates to novel cyclopentanophenathrene derivatives and to a process for the production thereof.

More particularly the present invention relates to ke-;

tonides of derivatives of androstane-2a,3a-diol and androstane-2;3,3,B-diol.

The novel compounds of the present invention which are anabolic-androgenic agents with a particularly favorable anabolic-androgenic ratio and which exhibit antiestrogenic and anti-gonadotrophic activities, relieve premenstrual tension, suppress the action of the pituitary gland and possess useful blood cholesterol lowering and anti-fibrillatory properties, are represented by the following formulas:

BIO

3,066,138 Patented Nov. 27, 1962 In the above formulas, R represents a lower alkyl' group, R represents hydrogen or methyl; A represents on; ii F-R or wherein R represents hydrogen or a hydrocarbon carboxylic acyl group containing less than 12 carbon atoms,

and R represents hydrogen or an alkyl, alkenyl or alkynyl group of less than 6 carbon atoms.

The acyl group is derived from hydrocarbon carboxylic acids containing less than 12 carbon atoms which may be saturated or unsaturated, of straight, branched, cyclic t or cyclic aliphatic chain, aromatic and may be substituted by functional groups such as hydroxy, alkoxy containing up to 5 carbon atoms, acyloxy containing up to 12 carbon atoms, nitro, amino or halogen. Typical ester groups are the acetate, propionate, enanthate, benzoate, trimethylacetate, t-butylacetate, phenoxyacetate, cyclopentylpro pionate, aminoacetate and B-chloropropionate.

The novel compounds of the present invention are prepared by the process illustrated by the following equationzj O i i R i v1 VII V: R =H X: R =H VI: R =hydrcarbon XI: R =hydrocarbon In the above formulas R, R and R have the same meaning as previously set forth.

In practicing the process outlined above, the starting compound which is A -androsten-l7-one or the 19-nor derivative thereof (I) is treated with iodine and a silver salt of an organic acid such as acetic acid in a suitable solvent preferably acetic acid, thus affording the corresponding androstane-ZfijB-diol derivative (II).

Following a second procedure, the starting compound (I) is treated with osmium tetroxide in the persence of pyridine and in a suitable solvent such as benzene at approximately 20 C. for a period of time of the order of 90 hours, furnishing the corresponding androstane- 20:,3ot-di01 derivative (VII). Treatment of the androstane-2,3-diol-17-one compound (II, VII) with a ketone such as acetone, ethyl methyl ketone, dicthyl ketone, ethyl amyl ketone and the like, in the presence of a mild acid such as perchloric acid, leads to the condensation of the carbonyl group with the glycol group thus afiording the corresponding dialkylmethylenedioxy derivative (III, VIII). Treatment of this latter compound with hydrazine hydrate and subsequent heating of the formed hydrazone to about 200 C., preferably by reflux in a solvent such as diethylene glycol, yields the corresponding 17-desoxo derivative (IV, IX).

Following a second procedure the dialkylmethylenedioxyandrostan-17-one compound (III, VIII) is reduced preferably with sodium borohydride affording the respective 17/3-hydroxy derivative (V, X).

A third reaction of the androstan-17-one derivative (III, VIII) with an alkyl, alkenyl or alkynyl magnesium halide, as for example, methyl magnesium bromide, vinyl magnesium bromide or ethynyl magnesium bromide in a solvent inert to the reagent such as benzene, furnishes the corresponding dialkylmethylenedioxy-l7a-alkyl, alkenyl or alkynyl-androstan-Ufi-ol (VI, XI).

The above obtained compounds with -a secondary hydroxyl (V, X) are conventionally acylated in pyridine with an acylating agent, as for example acetic anhydride or benzoyl chloride to yield the corresponding ester derivative.

The compounds of the present invention having a tertiary hydroxyl in the molecule (VI, XI) are conventionally acylated in the presence of p-toluenesulfom'c acid with an excess of an acylating agent such as the anhydr'ide of a hydrocarbon carboxylic acid of the type defined hereinbefore, thus furnishing the corresponding acylate.

The following specific examples serve to illustrate but are not intended to limit the scope of the present invention:

Example I A mixture of 13 g. of A -androsten-17-one, 50 cc. of dry benzene, 1 g. of osmium tetroxide and cc. of dry pyridine was kept at 20 C. for 90 hours. The solvents were then removed under reduced pressure and the residue heated under reflux for 4 hours with a mixture of 7.5 g. of mannitol, 7.5 g. of potassium hydroxide, 75 cc. of ethanol, 30 cc. of benzene and cc. of water. The mixture was then cooled, water was added and the product extracted with stane 2a,3a diol-17-one, androstane-Zfififl-diol-17-one,

Example 11 A solution of 5 g. of 19-nor-androsterone in 25 cc. of pyridine was cooled to 0 C. Under stirring, there was added 1.3 g. of tosyl chloride, the mixture was kept for 16 hours at 0 C., diluted with 100 cc. of chloroform, washed with dilute hydrochloric acid, water, aqueous sodium bicarbonate solution and again with water, dried over anhydrous sodium sulfate and then evaporated to dryness under reduced pressure. Thus there was obtained the crude tosylate of '19-nor-androsterone.

The total crude compounds was refluxed with 60 cc. of 'y-collidine for minutes under anhydrous conditions. The solution was cooled, and filtered. The filtrate was diluted with ether, washed with dilute hydrochloric acid, sodium carbonate solution and water. The dried extract was evaporated and the residue was chromatographed on neutral alumina. Crystallization of the solid fractions from acetone-hexane afforded 19-nor-A -androsten-17-one.

The foregoing compound was treated following the procedure described in Example I, thus furnishing 19-norandrostane-2a,3a-diol-17-one.

Example III 1.4 g. of iodine were added portionwise to a stirred mixture of 2.3 g. of silver acetate, 2 g. of A -androsten-17- one and 350 cc. of acetic acid. When the iodine had been consumed, 0.1 cc. of water was added and the mixture was stirred at 90 C. for 20 hours. There was then added 0.15 g. of sodium chloride in 1 cc. of water to the cooled mixture. The solution was then filtered and the filtrate diluted with water. The product was extracted with methylene chloride, the organic extract washed with dilute sodium carbonate solution, then with water, dried and evaporated to dryness. The residue was left standing overnight in cc. of 5% aqueous sodium hydroxide soluvtion. Water was added, the precipitate filtered olf, washed with water to neutral and dried under vacuum. Crystallization from methanol-ethyl acetate furnished androstane- 2;3,3fl-diol-17-one.

When applying the above technique to 19-nor-A -androsten-17-one, there was obtained 19-nor-androstane-2/9,3fldiol-17-one.

Example IV To cc. of acetone containing 1 g. of androstane-Za, 3a-diol-17-one, there were added 30 drops of 78% perchloric acid. After 1 hour at room temperature, 30 drops of pyridine were added and the resulting solution was evaporated to dryness under reduced pressure. 30 cc. of water were added to the residue and it was then extracted several times with 80 cc. of ethyl acetate. The combined extracts were washed to neutrality with water, dried over sodium sulfate and evaporated to dryness. Recrystallizations from the same solvent furnished 2a,3a-isopropylidenedioxy-andros'tan-l7-one.

When applying the foregoing technique to 19-nor-androand 19-nor-androstane-2fl,3,8-diol-17-one, there were correspondingly obtained 2:,3a-isopropylidenedioxy-19-norandrostan 17 one, 2,8,3,B-isopropylidenedioxy-androstan- 17-one, and 2fi,3fl-isopropylidenedioxy-19-nor-androstan- 17-one.

' Example V Following the procedure described in Example IV, but substituting acetone by diethyl ketone, there were treated androstane 2a,3oc diol-17-one, 19-nor-androstar1e-2a,3adiol-17-one, androstane-2fi,3,B-diol-l7-one, and 19-nor-androstane-2fl,3fi-diol-l7-one, thus furnishing respectively 26:,3a-(diethyl methylenedioxy)-androstan-l7-one, 2a,3ot- (diethyl methylenedioxy)-l9-nor-androstan-l7-one, 25,35- (diethyl methylenedioxy)-androstar1-l7-one, and 2,3,35- (diethyl methylenedioxy)-l9-nor-androstan-l7-one.

Example VI A solution of 1 g. of sodium borohydride in 3 cc. of water was added to an ice-cooled solution of 1 g. of 2a,3ot isopropylidenedioxy-androstan 17-one, in 120 cc. of methanol and the mixture was allowed to stand for 16 hours at room temperature. The excess reagent was decomposed by addition of acetic acid, the solution was concentrated to small volume in vacuo and diluted with water. The product was extracted with ethyl acetate, the extract was washed with water, dried and evaporated. The solid residue was purified by crystallization from acetonehexane to give ,3u-isopropylidenedioxy-androstanl7fi-ol.

When applying the above technique to 2a,3m-isopropylidenedioxy 19 nor androstan-l7-one, 2B,3 8-isopropy1- idenedioxy-androstan-17-one, and 25,3/3-isopropylidenedioxy-l9-nor-androstan-l7-one, there were correspondingly obtained 2a,3a-isopropylidenedioxy-19-nor-androstan-l7fi-ol, 2,8,3B-isopropylidenedioxy-androstan-175-01, and 2B,3B-isopropylidenedioxy-19-nor-androstan-l7fl-ol.

Example VII Following the technique described in Example VI, there were treated 20,3a-(dl6thYl methylenedioxy)-androstan- 17-one, 2a,3a-(diethyl methylenedioxy)-19-nor-androstan- 17-one, 2fi,3B-(diethyl methylenedioxy)-androstan-l7-one, and 25,3/3-(diethyl methylenedioxy)-l9-nor-androstan-l7- one, thus afiording correspondingly 2u,3a-(diethyl methylene'dioxy)-androstan-l7fi-ol, 2u,3a-(diethyl methylenedioxy)-19-nor-androstan-175-01, 25,3,8-(diethyl methylenedioxy)-androstan-17B-ol, and 2fl,3,B-(diethyl methylenedioxy)-19-nor-androstan-17fi-ol.

Example VIII A mixture of 1 g. of 2a,3a-isopropylidenedioxy-androstan-17-one, 2 g. of hydrazine hydrate, 1.2 g. of potassium hydroxide, 1.2 cc. of water and 1.2 cc. of diethylene glycol was heated under reflux for 45 minutes. It was then heated in an open flask until the temperature of the reaction mixture reached 200 C., a reflux condenser was attached, and refluxing was continued for a further 2 hours. The solution was cooled, water was added and the product isolated by extraction with ether. Recrystallization of the residue obtained after evaporation of the solvent from acetone-hexane aflorded 2u,3u-isopropy1- 'idenedioxy-androstane.

By the same technique, there were treated 2a,3a-isopropylidenedioxy-19-nor androstan-17-one, 2fl,3fl-isopropylidenedioxy-androstan 17 one, and 213,3,8-isopropylidenedioxy-l9-nor-androstan-l7-one, thus furnishing correspondingly 20,3ot-isopropylidenedioxy 19 nor androstane, 218,3fi-isopropylidenedioxy-androstane and 25,35- isopropylidenedioxy-l9-nor-androstane.

I Example IX When applying the technique described in the foregoing example to 2a,3a-(diethyl methylenedioxy)-androstan-17- one, 20:,3ec-(di6thYl methylenedioxy)-l9-nor androstan- 17-one, 2,9,33-(diethyl methylenedioxy)-androstan-17-one, and 28,354 diethyl methylenedioxy) -19-nor-androstan-17- one, there were respectively obtained 2m,3 ct-(diethyl 6 methylenedioxy)-androstane, 2a,'3a-(diethyl methylenedioxy) 19 nor-androstane, 2,8,3B-(diethyl. methylenedioxy)-androstane, and 25,35-(diethyl methylenedioxyy 19-nor-androstane.

Example X A solution of 5 g. of 20,3a-isopropylidenedioxy-androstan-17-one obtained according to Example IV, in 250 cc.

of thiophene-itree benzene was treated with 27.5 cc. of 4 N methylmagnesium bromide in ether and the mixture was refluxed with the exclusion of moisture for 3 hours. The cooled mixture was cautiously treated with excess aqueous ammonium chloride solution and the product isolated by ethyl acetate extraction. The extract was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness. 1

Recrystallization from methylene chloride-hexane afforded 2a,3a-isopropylidenedioxy-17rx-methyl androstan- -01.

Following the above procedure, there were treated the hereinafter listed starting compounds with the indicated Grignard reagent, affording the corresponding products set forth below:

Starting compound Grignard reagent Product 20:, 3n-isopropylidene- Vinylmagnesium 2a, 3 -isopropylidenedioxy-androstan-U- bromide. dioxy-lh-vinylone. androstan-flfl-ol.

Do Ethynyl magnesium 2a, 3wisopropylidenebromide. dioxy-lh-ethvnylandrostau-Hfi-ol. 2m, 3u-isopropylidenedi0xy-17a-meth 5 1-19- 20:, 3a-isopropylidene- Methyl magnesium dioxy-iQ-nor-androbromide.

bromlde. dioxy-17a-ethynyl-19- nor-androstan-17fi-ol. 25, 3B-isopropylidene- Methyl magnesium 219, 3B-isopropylidene: dioxy-androstan-U- bromide. dioxy-l'ia-methylone. androstan-178-ol.

Do Vinyl magnesium 2B, 3fl-isopropylidenabromide. dioxy-im-vinylandrostan-IZB-ol. Do Ethynyl magnesium 2,9, 3fl-isopropylidenebromide. dioxy-lhethynylandrostan-17B -ol. 2B, 3fl-isopropylidene- Methyl magnesium 2p, 3 8-isopropyl1denedioxy-lQ-uor-androbromide. dioxy-17a-methyl-19- stan-I7-one. nor-androstan-UB-ol. Do Vinyl magnesium 2B, 3B.-isopropylidenebromide. dioxy-17a-viny1-19- nor-androstan-UB-Ol. Do Ethynyl magnesium 2a, 3a-isopropylidenebromide. dioxy-lhethynyl- 19- nor androstan-flfl-ol. 2a, Zia-(diethyl methyl- Methyl magnesium 2a, Sat-(diethyl methylene-dioxy)-androbromide. enedioxy)-17a-methylstan-17-one. androstan-Nfl-ol.

Do Vinyl magnesium 20:, 3a-(diethyl methylbromide. enedicxy) -17a-v1nylandrostan-HB-ol. Do Ethynyl magnesium 2a, lieu-(diethyl methylbromide. enedioxy)-17a-ethynyl androstan-Ufl-ol. 2a 3a-(diethyl methyl- Methyl magnesium 2Q, 3a-(diethy1-methylene-dioxyHQ-norbromide. enedioxy)- Her-methyl androstan-17-one. l9-uor-androstan-17fi- 01. Vinyl magnesium 2a, 3a-(diethyl-methyi- 2B, fill-(diethyl methylenedioxy)-17a-methyl- 19-nor-androstan-17fi- 01. 2B, 3B-(diethyl-methyl- 2B, 3B-(dietl1yl methylene-dioxy)-19-norandrostan-17-one.

Methyl magnesium bromide.

Do Vinyl magnesium bromide. enedi0xy)-l7a-v1nyllil-nor-androstan-UB- o. i Do Ethynyl magne 2B, 3B-(diethylmethylsium bromide.

Example XI A mixture of 1 g. of 2a,3a-isopropy1idenedioxy-androstan-l75-ol, 4 cc. of pyridine and 2 cc. of acetic anhydride was kept at room temperature overnight, poured into ice water, the formed precipitate was filtered, washed with water and dried. Crystallization from acetone-hexane gave the acetate of 2a,3ot-isopropylidenedioxy-androstan- 175-01.

By the above technique there were treated the starting compounds listed below, thus furnishing the corresponding products hereinafter disclosed:

Starting compounds Products 20:, 3a-isopropylidenedioxy-IQ- nor-androstan-lh-ol 25, 35-isopropy1idenedioxyandrostan-Uflol 2B, 35-isopropylidenedioxy-19- nor-androstan-175-ol 20:, 3a-(dicthyl methylenedinxy)-19-nor-androstau-17fl-0l 25, 35-(diethyl metl1y1cncdioxy)- androstnn-UB-ol 25, 35-(diethyl methylenedioxy)- 19-nor-andr0stan-17fl-0l 17-acetate of 2a, 3a-isopropylidcncdioxy-lQ-nor-zmdrostan-170ml 17-acetate of 2B, 35-is0propy1idcnedioxy-androstan-li'B-ol 17-acetate of 25, 35-isopropylidcnedioxy-l9-nor-androStan-17B-01 17-acetate f 20:, 3a-(cliothyl methylenedioxy)-androstan-17B-ol 17-acetate of 2a, 3a-(diethyl methylenedioxy)-19-nor-androstan-17B-ol 17-acetate of 25, 35-(dietbyln1cthylenedioxy)-androstan-17/3-ol 17-acetate of 25, 35-(diethyl methylonedioxy)-19-nor-androstau-l7B-o1 Example XII Following the procedure described in Example XI, except that acetic anhydride was substituted by propionic anhydride, caproic anhydride, cyclopentylpropionic anhydried, and benzoyl chloride, there were correspondingly obtained the l7-propionates, l7-caproates, l7-cyclopentylproprionates and 17-benzoates of the starting compounds mentioned in the same example.

Example XIII Starting compounds Products 17-acetate of 20:, 3a-isopropylidcnedi0xy-lh-vinyl-androstan-l75-01 17-acetate of 20:, 3a-isopropylidenedioxydh-methyl-lQ-nor-au drostan-175-01 17-acetate of 2a, 3a-is0pr0pylidenedioxy-l7a-viny1-19-nor-andr0stan- 2a, 3a-isopropylidenedioxy-li'avinyl-qndrostan-Ufl-ol 2a, 3a-is0propylidenedioxy-lhethynyl-androstan-ITB-ol 2a, 3a-isopropylidcnedioxy-Hamethyl-IQ-nor-androstan-l75- 01 2a, 311-1sopropylidenedioxy-lhviny1-19-n0r-androstan-175-0l 17-acctate of 201, 3a-isopropylidenedioxy-l7a-ethyny1-19-nor-a11dro- Stan-17501 l7-acetatc of 25, 35-isopropylidencd1i0xy-17a-methyl-androstan-UB- 0 l7-acetate of 25, 35-isopropylidenedioxy-lTa-Vinyl-androstan-175-ol 17-acetate of 25, 35-isopropylidcnedi0x3i-17a-cthynyl-androstan- 17-acetate 0f 25, 35-isopropy1idcnedioxy-17a-methyl-19-110r-androstan-l'ifl-ol 17-acetate of 2B, 3fl-isopropylidenedioxy-l7a-viny1-19-nor-andr0stan- 2a, 3a-isopropylidencdioxy-17aethynyl-ISJ-nor-androStan-175- 0 25, 35-isopropy1idenedioxy-17amethyl-androstan-Uflol 25, SB-isopropylidenedioxy-17avinyl-androstan-Ufi-ol 25, 35-150propylidenedioxy-lhethynyl-androstan-175-ol 25, 35-180propylidenedioxy-flamethyl-l -nor-andr0stan-175- 01 25, 3B-isopropylidenedioxy-Uavinyl-ISJ-nor-androstan-17501 17-acetate of 2a, 3a-isopropylidenedioxy-l7a-ethynyl-l -nor-androstun-17501 17-acetate of 2a, 3a-(diethy1 methylenedioxy)-17a-metl1y1-androstan- 176-01 20:, 3a-is0propy1idenedi0xy-17aethynyl-IQ-nor-androstan- 175-01 20:, 3a-(diethyl methylenedioxy)-17a-methyl-androstan- 20:, 3a-(die-thy1 methylene- 17-acetate of 2a, 3a-(diethy1methy1- dioxy)-l7a-vinyl-a.ndr0stanenedioxy)-17a-vinyl-androstan- 175-01 175-01 Starting compounds Products 204, 3a-(diet1yl methylenedioxy)-17a-ethynyl-androsta11- 25, 35-(diethylmethy1enedinxy)-17a-viuy1-androstan- -01 25, 3B-(tlietbyl methylenedioxy)-lTa-rn ct'uyl-lO-norandrostan-lm-ol 2 8, 35(dict1yl methylenedioxy)-17a-vinyl-19-norandrostan-IZB-ol 25, SB-(dietiiyl methylenedioxy)-17a-ethynyl-19-norandrostan-175-ol 17-acetate of 20:, 3a-(diethy1mctby1- enedioxy)-17a-ethynyl-androstanl7-acetate of 2a, 3a-(dlcthyl methylenedioxy)-17a-methy1-19-noraudrostan-l'ifl-ol 17-acetatc of 2a, fi -(dlethyl methylenedioxy)-17a-vmyl-19-norandrostan-NB-ol 17-acetate of 2a, 3a-(diethyl methylenedioxy)-17a-ethynyl-19-norandrostan-175-ol 17-acetate of 25, 3B-(dlethy1methylenedicxy)-17a-rnethyl-androstan- 1715-01 17-acetatc of 25, 35-(dicthy1 methyleneclioxy)-17a-vinyl-androstan- 76-01 17-acetate of 25, 35-(diet11yl methyl- (12171;dHoxy)-l7a-ethynyl-androstan- -0 17-acetate of 2/3, 35-(dietl1y1 methylenedioxy)-17a-methy1-19-norandrostau-l75-ol 17-acctate of 25, 3fl-(diethyl methylonedi0xy)-17a-viuyl-19-norandrostan-HB-ol 17-acetate 01 25, 35-(diethyl methyl- GHGdlOXY)-17a-6tl1YI1Yl-19-I10fandrostan-175-0l Example XIV wherein R is a lower alkyl group; R is a member of the group consisting of hydrogen and methyl; and A is selected from the group consisting of methylene 2) carbonyl 0 and the group wherein R is a member of the group consisting of hydrogen and a hydrocarbon carboxylic acyl group of less than 12 carbon atoms and R is selected from the group consisting of hydrogen and an alkyl, alkcnyl and alkynyl group of up to 6 carbon atoms.

2. 2a,3a-isopr0pylidenedioxy-androstan-17-one.

3. 2a,3oz isopropylidenedioxy 19 nor androstan- 17-one.

4. 2a,3u isopropylidenedioxy androstan 175 01.

5. 20:,30: isopropylidenedioxy 19 nor androstan- 175-01.

6. 2a,3a isopropylidenedioxy 17oz methyl androstan-l75-ol.

7. 211,30: isopropylidenedioxy 17a vinyl androstan-175-ol.

8. 211,30; isopropylidenedioxy 17a ethynyl androstan-l7 3-ol.

9. 20:,30: isopropylidenedioxy 17a methyl 19 -norandrostan-175-ol.

wherein R is a lower alkyl group; R is a member of the group consisting of hydrogen and methyl; and A is selected from the group consisting of methylene (-CH carbonyl and the group wherein R is a member of the group consisting of hydrogen and a hydrocarbon carboxylic acyl group of less than 12 carbon atom-s and R is selected from the group consisting of hydrogen and an alkyl, alkenyl, and alkynyl group of up to 6 carbon atoms.

13. 25,35 isopropylidenedioxy androstan 17 one.

14. 25,35 isopropylidenedioxy 19 nor audrostan- 17-one.

15. 25,35 isopropylidenedioxy androstan 175 01.

16. 25,35 isopropylidenedioxy 19 nor -androstan- 175-01.

17. 25,35 isopropylidenedioxy 17cc methyl androstan-175-ol.

18. 25,35 isopropylidenedioxy 17a vinyl androstan-175-ol.

19. 25,35 isopropylidenedioxy 17a ethynyl androstan-175-ol.

20. 25,35 isopropylidenedioxy 17a methyl 19- nor-androstan-175-o1.

21. 25,35 isopropylidenedioxy 17cc vinyl 19 norandrostau-l-ol.

22. 25,35 isopropylidenedioxy 17a ethynyl 191 nor-androstan--ol.

No references cited. 

1. A COMPOUND OF THE FOLLOWING FORMULA:
 12. A COMPOUND OF THE FOLLOWING FORMULA: 